Project Summary/Abstract Understanding the complex neural circuits involved in drug addiction is a major challenge which, if met, could provide insight into the disease and guidance for treatment. Efforts focused on understanding mechanisms that underpin addictive behaviors have contributed to illuminating relevant brain circuitry, including connections between the ventral tegmental area, nucleus accumbens, medial prefrontal cortex, amygdala, and hippocampus. While much is known and emerging about this circuitry relevant to addiction, the intrinsic complexity ? interconnections between a number of distinct and widely separated brain regions ? make difficult high-resolution circuit-wide longitudinal studies of addiction that track neuron-level changes across the system. In our proposed investigations, we set forth to develop and apply an innovative technology, syringe-injectable mesh electronics, to overcome previous limitations of in-vivo chronic recording and thereby enable stable long-term mapping and modulation of neuronal signals with single-neuron resolution across the multiple brain regions associated with addiction. First, we plan to investigate simultaneous targeting of critical regions of the rodent brain involved in drug addiction with minimal chronic immune response using syringe-injectable mesh electronics, including demonstration of targeted injection of mesh electronics probes that each bridge simultaneously multiple brain regions involved in the overall addiction circuitry, such as the medial prefrontal cortex to nucleus accumbens and hippocampus to amygdala. Second, we propose to demonstrate long-term stable simultaneous recording from these critical regions of the rodent brain defining the addiction circuitry in mice, to quantify correlations between neurons within and between different areas of the overall circuitry, to demonstrate the ability to modulate recorded signals using stimulator electrodes integrated within the mesh electronics probes, and to record and subsequently quantitatively analyze changes in the signals across multiple circuit regions following alcohol self-administration and subsequent cessation in mice. By opening up the potential for simultaneous stable chronic recording from neurons in a minimally invasive manner from key brain areas during longitudinal studies, our proposed work can provide a new technology as well as unique data to illuminate system-wide changes within the addiction circuitry. These innovative technology capabilities will help to advance circuit-level studies of addiction by other researchers, and moreover, the development of this new technology could serve as a means for more effective treatments based on electrical stimulation to modulate specific circuit components that might preclude chronic abuse and relapse.